HIV/AIDS, comorbidity, and alcohol: can we make a difference?

Alcohol use is common among people infected with HIV and plays an important role in their health outcomes. Because alcohol use complicates HIV infection and contributes to comorbid diseases, it is important for researchers and practitioners to understand these interactions and to integrate alcohol treatment with medical management of long-term HIV infection and associated comorbidity. The Veterans Aging Cohort Study (VACS) is a large, multisite study of the effects of alcohol use on HIV outcomes in the broader context of aging. A multilevel strategy intervention trial is needed to address the many modifiable implications of alcohol consumption among those receiving treatment for HIV.

A lcohol use is common among people at risk for, and aging with, human immunodeficiency virus (HIV) infection and plays a central modifiable role in their health outcomes (Braithwaite et al. 2007;Conigliaro et al. 2003Conigliaro et al. , 2004Cooper and Cameron 2005;Justice et al. 2004Justice et al. , 2006bMcGinnis et al. 2006;Rees et al. 2001;Samet et al. 2004;Shaffer et al. 2004). Past and present alcohol consumption directly influences HIV progression and survival by altering timing of and adherence and response to medication designed to minimize levels of HIV in the body (i.e., antiretroviral treatment [ART]) (Bean 2000;Braithwaite et al. 2005Braithwaite et al. , 2007Braithwaite et al. , 2008Cook et al. 2006;Kresina et al. 2002;Samet et al. 1998Samet et al. , 2003. Alcohol use also influences patient outcomes by increasing the risk for HIV and antiretroviralassociated comorbidities, including liver disease, cardiovascular and cerebrovascular disease, pulmonary disease, bone disease, and cancer (Conigliaro et al. 2003(Conigliaro et al. , 2006Justice et al. 2006b). People with HIV have a lower tolerance for alcohol (Braithwaite et al. 2008) yet maintain heavy levels of consumption as they age (Green 2009). The cumulative effects of past and current alcohol consumption is likely to increase now that patients with HIV infection are expected to live 20 to 30 years on ART (Hogg et al. 2008).
Health care providers can help to mitigate the harmful effects of alcohol use in patients with HIV. A growing body of research has demonstrated that behavioral and pharmacologic interventions for alcohol can be implemented successfully in primary care and officebased settings (see Samet and Walley, in this issue). However, practitioners and researchers must adapt and coordinate such interventions to the complex clinical context of HIV infection. This will require prioritization and integration of alcohol treatment with medical management of longterm HIV infection and associated comor bidity. The only reasonable way to integrate and jointly prioritize treat ment for HIV, comorbid disease, and alcohol use is to estimate the impact each condition has on the patient's risk of morbidity and mortality and thus help inform patient and provider decisionmaking (Braithwaite et al. 2007;Justice 2006). Researchers must therefore develop methods to prioritize, integrate, and coordinate treatment for alcohol, HIV, and associated comorbid conditions.

HIV/AIDS, Comorbidity, and Alcohol
Because HIV infection has become a complex chronic disease in which alcohol has a multifaceted impact on health outcomes, strategy implemen tation studies are needed. Strategy implementation studies combine behavioral and pharmacologic methods to decrease alcohol consumption with clinical strategies to mitigate the short and longterm effects of alcohol on morbidity and mortality. Longterm (i.e., longitudinal) observational studies are particularly useful in helping to characterize HIVinfected populations at risk and their alcoholassociated disease trajectories. Further, data from observational studies can suggest means of objectively gauging the effects of this combined approach. This article reviews the prevalence of alcohol use among people with HIV and the complex and interacting role of alcohol use in HIV and selected comorbid diseases, describes ongoing plans for continued longitudinal observation, and, finally, discusses the authors' plan to develop multilevel strategy implementation trials within the Veterans Aging Cohort Study (VACS).

Prevalence
The majority of people receiving care for HIV infection report current alcohol consumption (i.e., consuming alcohol during the previous 12 months). Among people coinfected with hepatitis C virus (HCV) or with evidence of liver injury, the proportion comprising current alcohol users is even higher (Conigliaro et al. 2006;Goulet et al. 2005). In a national sample of patients with HIV, 8 to 12 percent were classified as current heavy drinkers, a rate approximately twice that of the U.S. national average (Burnam et al. 2001;Galvan et al. 2003). The lifetime prevalence of alcohol use disorders in patients with HIV is two to three times that of the general popu lation (Conigliaro et al. 2006;Connors and Volk 2003;Isaacson and Schorling 1999;O'Connor and Schottenfeld 1998;Reid et al. 1999Reid et al. , 2002. Finally, in contrast to findings from popula tions of people without HIV, there is no evidence of a protective effect from alcohol in people with HIV (Ellison 2002).

Alcohol and Medication Nonadherence
Alcohol problems in HIVinfected patients are associated with poor adher ence to combination antiretroviral therapy (CART) medications (Braithwaite et al. 2005(Braithwaite et al. , 2007(Braithwaite et al. , 2008Cook et al. 2001). The VACS, a large National Institute on Alcohol Abuse and Alcoholism (NIAAA)funded national sample of HIVinfected and HIV negative patients (Justice et al. 2006a), examined the relationship between alcohol consumption and medication adherence and found that adherence was lower on days on which patients drank heavily and on the following day. The effect of alcohol was more pro nounced in HIVinfected individuals; non-binge drinkers were 1.8 times more likely to have lower adherence, and binge drinkers were 4.3 times more likely to have lower adherence (Braithwaite et al. 2005). Further, alcohol consumption was the most significant predictor of CART medica tion adherence, with the greatest adher ence associated with recent abstinence from alcohol. A separate study noted that adjusting alcohol quantity for level of average selfreported consumption and selfreported threshold for intoxi cation improves the association between alcohol and nonadherence (Braithwaite et al. 2008;Justice et al. 2006a). Heavy drinking in HIVinfected patients also is associated with poor treatment response, as evidenced by lower counts of immune cells (i.e., CD4 lympho cytes) and higher HIV RNA (Samet et al. 2003). In turn, it has been shown that people who stop drinking have an improved response to HIV therapy (Samet et al. 2003).

Alcohol and Antiretroviral Resistance
Ongoing heavy drinking is strongly associated with poor CART adherence. Suboptimal CART adherence not only leads to HIV progression but also to antiretroviral resistance (Braithwaite et al. 2006(Braithwaite et al. , 2007. HIV drug resistance results from mutations that arise in the viral proteins targeted by antiretroviral medications. Antiretroviral resistance diminishes the effectiveness of treatment for individual patients and for individuals subsequently infected with these viral strains. Mutations can cause resistance to a single medication or an entire class of antiretrovirals. HIV drug resistance can lead to an inability of the drug or class of drugs to suppress the HIV virus and, therefore, limits future treatment options.

Alcohol, Risky Sexual Behavior, and HIV Transmission
Alcohol use also is strongly associated with risky sexual behavior among peo ple with HIV infection (Cook et al. 2006;Leigh 1990;Rees et al. 2001;Stein et al. 2005). Because people using alcohol are less likely to adhere to their antiretroviral medication, they are more likely to have a high virus load, including resistant virus. For instance, in one study of 168 people with viral resistance, frequent alcohol use was associated with unprotected intercourse with HIVinfected partners (ChinHong et al. 2005). Therefore, people with HIV who consume significant amounts of alcohol pose a particularly high risk of HIV transmission, and the virus transmitted already may be resistant to at least some forms of ART.

HIV, Aging, and Alcohol
Many studies have found that people with HIV experience agerelated comorbid disease, organ system func tional decline, and frailty at an earlier age than demographically similar control subjects (Appay et al. 2007;Bestilny et al. 2000;Desquilbet et al. 2007;Effros 2004;Oursler et al. 2006). This is likely to be accentuated among those consuming harmful amounts of alcohol. Lifetime patterns of substance abuse differ for people with HIV infec tion compared with demographically similar uninfected individuals (Green 2009). Specifically, patterns of heavy consumption continue into middle and older ages and are paralleled by similar patterns of drug and tobacco use. Yet people with HIV infection have lower tolerance for alcohol (Braithwaite et al. 2008).
Much of the continuing morbidity among patients receiving CART has been attributed to chronic inflamma tion resulting from the depletion of tissue important in immune cell gen eration (i.e., lymphoid tissue). This depletion causes increased intestinal permeability (Deeks 2009;Deeks and Phillips 2009;Kuller et al. 2008;Weber et al. 2006), which also can occur with alcohol use, leading to similar medical consequences (Purohit et al. 2008). Taken together, these observa tions suggest a larger harmful effect of alcohol among middleaged and older individuals with HIV infection than among demographically similar unin fected control subjects (see figure 1).
Similarly, a large proportion of people with HIV infection who are not currently drinking have a sub stantial history of alcohol abuse and dependence and are more likely to report that they stopped drinking because they were too ill to continue. As a result, many HIV patients experience alcoholrelated medical consequences even though they may no longer be drinking (Justice et al. 2006b). Providers often fail to detect current alcohol consumption; they almost never ask about past con sumption (Conigliaro et al. 2003). As a result, they are unlikely to detect organ system injury resulting from prior alcohol consumption (Corrao et al. 2004).

HIV, Alcohol, and Comorbid Disease
HIV and alcohol use are associated with increased risk for various types of disease. Some of these comorbidities are described below. who are aging with HIV infection from presenting health conditions through interacting disease processes to cumulative organ system injury, advanced clinical disease, and, eventually, death. The VACS Risk Index attempts to integrate and summarize the total disease process in order to better reflect risk of morbidity and mortality and to facilitate the identifi cation and modification of risk.

Liver Disease
HIV infection and particular ARTs substantially increase the risk for inci dence and progression of liver disease (Sulkowski 2008a, b;Sulkowski et al. 2007). Even low levels of liver injury are associated with substantial increases in risk of mortality among patients with HIV infection (Justice et al. 2009). These levels of injury are common among HIVinfected patients receiving care due to multiple causes, including alcohol use viral hepatitis, ART toxicity, and, likely, nonantiretroviral medica tion toxicity. Morbidity and mortality associated with alcoholinduced liver injury is well described and is marked by progressive liver inflammation and the formation of scar tissue (i.e., fibrosis), leading to cirrhosis and its complications. Among people with chronic HCV infection, regular alcohol use contributes to an increased risk of cirrhosis, inability of the liver to recover from damage (i.e., liver decompensation), cancer, and death (DeufficBurban et al. 2007;Sulkowski 2008a, c). Although liver cell injury is increasingly recognized as a particularly important source of morbidity and mortality among people with HIV, it is largely ascribed to coexisting viral hepatitis and medication associated liver damage (e.g., antiretro viral drugs). The independent impact of varying and even low levels of alcohol consumption on progression of this injury has not always been clearly iden tified. Lim and colleagues (2008) recently noted that liver injury and fibrosis increase directly with increasing levels of alcohol consumption. Significant increases in advanced fibrosis or cirrhosis are found at all levels of alcohol expo sure among people with HIV only (8.6 percent), HCV only (13.8 percent), and HCV-HIV coinfection (31.8 percent). In multivariate analysis, after controlling for HCV and HIV infections, alcohol abuse or dependence represented the strongest predictor of advanced fibrosis (Lim et al. 2008). Based on evidence that even low levels of alcohol can act synergistically with HIV, HCV, and CART to cause hepatoxicity, strate gies that can decrease the adverse impact of alcohol, such as effective treatments for alcohol consumption, are likely to yield substantial benefits. HIV

Cancer
HIV infection is associated with an increased risk for many common cancers (anal, cervical, liver, colon, lung, and leukemia), not all of which are associated with viral infections (e.g., anal, cervical, and liver cancer) (Bedimo et al. 2009;Patel et al. 2008). Increased alcohol consumption has been associated with cancers of the digestive tract (e.g., mouth, pharynx, larynx, esophagus), upper airway, breast, and liver (Corrao et al. 2004). A recent metaanalysis (Bagnardi et al. 2001) was not able to determine a level of alcohol consumption below which no risk for cancer was evident.
In addition to the malignancies noted above, researchers found increases in the risk for cancers of the stomach, colon, rectum, and ovaries. The meta analysis was able to document that study participants who consumed four drinks per day had an increased risk for cancer at multiple sites.

The Role of Longitudinal Observational Analyses Such As VACS
The review above highlights specific areas in which data on the association between alcohol and multiple medical conditions exist. Nonetheless, the exist ing literature often is limited by its crosssectional nature, limited follow up, or limited information regarding alcohol consumption and alcohol related disorders. Therefore, longterm observational studies, including study participants with and without HIV, can play an essential role in providing information about the role of alcohol in HIV and comorbid medical condi tions. These studies may help elucidate the impact of alcohol consumption and other behaviors on the progression of common medical conditions. The advantage of observational methods is that they provide information about the natural history of these conditions and the realworld efficacy of standard treatments. Whereas other research designs such as randomized clinical tri als can provide information on treat ment efficacy, observational studies pro vide unique information regarding causal associations, prognosis, risk, and the effect of treatment in populations that are more diverse than those often included in clinical trials. In this way, observational methods can provide unique information that can be used to inform intervention studies designed to maximize treatment strate gies and target risk factors and exposures.

What Is VACS?
The VACS is a study of HIVpositive patients attending infectious disease clinics and age, race, and sitematched HIVuninfected patients in general medicine clinics (Justice et al. 2006a

What measures are available to explicate the influence of alcohol on overall health in people with HIV infection?
A major difficulty in alcohol research is the lack of a goldstandard measurement for exposure. Alcohol levels in the blood stream reflect only recent exposure, and other biomarkers that reflect longerterm exposure are not sensitive or specific (Allen et al. 2003;Fiellin et al. 2000;Figlie et al. 2002). As a result, intervention trials have relied on patient selfreport of alco hol consumption, most often measured in drinks per day (Maisto et al. 1995).
Although most studies have demon strated that alcohol interventions can affect patient reports of drinks per day over short and intermediate terms (1 to 12 months), few have documented a change in morbidity or mortality. Despite research demonstrating that shorter selfreport measures perform as well as longer, more involved sur veys (Gordon et al. 2001;Maisto et al. 2008), concerns about substantial reporting bias remain. For example, control groups demonstrate decreasing reports of drinks per day over the course of most alcohol intervention studies. Therefore, it remains unclear whether, in the face of repeated requests to report alcohol consumption, respondents simply report fewer drinks or have truly modified their drinking behavior (Clifford and Maisto 2000;Cliffort et al. 2007). It also is unclear whether the reported changes in drinking behavior are sufficient to change longterm clinical outcomes.
Biomarkers. Biomarkers provide the means to assess clinical effects of alcohol and aging directly and to prioritize these effects according to their likely cumulative effect on morbidity and mortality. The advantage of using biomarkers is that they may be able to provide informa tion about important clinical changes before the changes are obvious to patients or health care providers. Therefore, biomarkers can serve as an "early warn ing system" in clinical trials and clinical care to help predict morbid events.

VACS Risk Index. VACS has recently
developed an index of commonly avail able clinical lab values termed the VACS Risk Index (Justice et al. 2009). The VACS Risk Index is designed to be a prognostic index that reflects alcohol, HIV, and comorbid disease-related physiologic injury. The index includes indicators of liver injury, viral hepatitis, AIDSdefining illnesses (e.g., pneumo cystis pneumonia, toxoplasmosis), renal injury, bone marrow injury, and immune suppression.The VACS Risk Index has demonstrated predictive accuracy for mortality among veterans in care with HIV infection on par with several established risk indices devel oped for other important clinical popu lations. For 30day mortality, the VACS Index is as discriminating of mortality as the APACHE index is among intensive care unit patients. It is more discrimi nating than the Charlson Comorbidity Index is for 1year mortality among a general sample of individuals admitted to the hospital. Because it integrates immunologic virologic measures (i.e., CD4 cell count and viral load), disease measures (i.e., AIDSdefining condi tions and viral hepatitis), and measures of organ system function (renal insuffi ciency, liver injury, and anemia), it reflects the multifaceted direct physio logic effects of alcohol and important interactions with viral hepatitis, HIV disease progression, and ART, including the resulting effects of poor adherence to ART. Most importantly, because the index focuses on biomarkers, it cap tures the summary biologic effect of alcohol on the individual rather than measuring standard units of exposure.

VACS Plans for Strategy Implementation Trials
A multilevel, strategy intervention trial is required to address the many modifi able implications of alcohol consump tion among those receiving treatment for HIV. Alcohol has systemic biologic effects and is associated with multiple highrisk behaviors, including other substance use, risky sex, and medication nonadherence. Levels of alcohol con sumption not associated with harm among those without HIV infection may be harmful among infected indi viduals. Importantly, alcohol's harmful effects are not likely to be uniform among HIVinfected individuals. Finally, patients who are not currently drinking may still be suffering longterm biomedi cal complications from past alcohol abuse or dependence. Therefore, it is important to address ongoing injury from other sources (e.g., medication toxicity, untreated chronic viral hepatitis). The measure of selfreported drinks per day does not capture any of these factors. By using the VACS index to estimate risk of mortality, to identify the degree to which alcohol represents a significant and modifiable risk of mor bidity and mortality in our patients, and to act as a surrogate marker for morbid events, we can design more informative and effective intervention studies.
The authors propose to use the index as part of a fully integrated and staged behavioral, pharmacologic, and biomedical intervention designed to decrease alcohol use and minimize morbidity and mortality. The index will be used to characterize overall risk of mortality and proportion of risk attributable to alcohol. Changes in the index over time will be used as the primary outcome (integrated surrogate marker) of the study, and we will conduct a validation analysis of the association between selfreport ed measures of alcohol consumption and changes in the index. Thus, the index will be both an outcome and a means of motivating behavior change (e.g., decreasing or stopping alcohol consumption and improving medica tion adherence). The index also will provide a means of motivating providers to refer patients for more intensive alcohol treatment and to prioritize factors likely exacerbating effects of alcohol (e.g., HCV and HBV infection, depression, anemia, treatment toxicity).
Because organ system injury and mortality are accelerated among HIV patients, they provide an ideal popu lation in which to test the use of a biomarker index. The authors are currently beginning feasibility studies and evaluating the discrimination of the index for important clinical out comes (i.e., functional status, frailty, hospitalizations, quality of life) and it applicability in HIVnegative and nonveteran populations. Should this work prove successful, the approach may prove widely generalizable. The goal of the strategy implementation study will be to combine components that have individually demonstrated efficacy in order to maximize improvement in outcome. As such, we anticipate that these interventions will be focused on the science of implementation and demonstrating effectiveness among diverse popula tions of patients. ■